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Antimicrobial Agents and Chemotherapy, August 2008, p. 2861-2869, Vol. 52, No. 8
0066-4804/08/$08.00+0 doi:10.1128/AAC.00210-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Preclinical Evaluation of 1H-Benzylindole Derivatives as Novel Human Immunodeficiency Virus Integrase Strand Transfer Inhibitors 
Anneleen Hombrouck,1
Barbara Van Remoortel,1
Martine Michiels,1
Wim Noppe,2
Frauke Christ,1
Anders Eneroth,3
Britt Louise Sahlberg,3
Kurt Benkestock,3
Lotta Vrang,3
Nils Gunnar Johansson,3
Maria Letizia Barreca,4,5
Laura De Luca,4
Stefania Ferro,4
Alba Chimirri,4
Zeger Debyser,1,2* and
Myriam Witvrouw1,2
Division of Molecular Medicine, Katholieke Universiteit Leuven, Flanders, Belgium,1 Interdisciplinair Research Center, Katholieke Universiteit Leuven Campus Kortrijk, Flanders, Belgium,2 Medivir AB, Lunastigen 7, Huddinge, Sweden,3 Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy,4 Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy5
Received 14 February 2008/ Returned for modification 14 March 2008/ Accepted 30 May 2008
We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC251 [SIV(MAC251)]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(IIIB) in MT-4 cells at a 50% effective concentration (EC50) of 0.60 µM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC251) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC50, 0.30 to 0.38 µM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
* Corresponding author. Mailing address: Division of Molecular Medicine, Katholieke Universiteit Leuven, Flanders, Belgium. Phone: 32-16-33.21.83. Fax: 32-16-33.21.31. E-mail: Zeger.Debyser{at}med.kuleuven.be
Published ahead of print on 9 June 2008.
Antimicrobial Agents and Chemotherapy, August 2008, p. 2861-2869, Vol. 52, No. 8
0066-4804/08/$08.00+0 doi:10.1128/AAC.00210-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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